Heparin versus
placebo for acute coronary syndromes.
K Magee, D Moher, B Rowe.
DOI: 10.1002/14651858.CD003462
David
K. Cundiff, MD
Date received: July 27, 2007
No review has resulted from this important protocol. However, the review titled, “Low molecular weight heparins versus unfractionated heparin for acute coronary syndromes,” was published four years ago. If heparin doesn’t work compared with placebo for acute coronary syndromes, there would be no need to do the subsequent comparison of heparin with low molecular weight heparins.
In the subsequent unfractionated heparin versus LMWH Cochrane review, the same authors cited only two RCTs to justify the use of heparin in ACS. (1) Theroux, et al randomized 479 patients with unstable angina to ASA, ASA + heparin, and placebo. No deaths occurred in the groups receiving ASA, whether they received heparin or not, while 3.3% of ASA + heparin patients had major bleeding compared with 1.7% of those receiving heparin alone.1 (2) The “RISC Group” randomized 796 men with unstable coronary artery disease (unstable angina or non-Q-wave myocardial infarction [MI] ) to double-blind placebo-controlled treatment with oral aspirin 75 mg/day and/or 5 days of intermittent intravenous heparin. According to the abstract, “The risk of MI and death was reduced by aspirin. After 5 days the risk ratio was 0.43 (confidence intervals, 0.21-0.91), at 1 month 0.31 (0.18-0.53), and at 3 months 0.36 (0.23-0.57). Aspirin reduced event rates in non-Q-wave MI and unstable angina independently of electrocardiographic abnormalities or concurrent drug therapy. Heparin had no significant influence on overall event rate, although the group treated with aspirin and heparin had the lowest number of events during the initial 5 days.”2
Because of excluding observational studies from consideration in the safety analysis, the bleeding complications will be very likely understated. Large observational studies are also required to evaluate risk of heparin induced thrombocytopenia with thrombosis (HITT). Besides thrombocytopenia, HITT should be included as an outcome measure. The primary endpoint, which determines the main conclusions of the review, is not stated.
Compared with ASA alone in ACS patients, heparin is evidence-based to increase major bleeding but not to reduce deaths or heart attacks.
Feedback #2 (July 21, 2008) After publication of the review.
I thank Drs. Magee, Moher, and Rowe for completing the review.
The phenomenon of reactivation of unstable angina after the discontinuation of heparin has been described by Theroux.3 Even when aspirin is added to heparin in patients with unstable angina, the benefit of the heparin in preventing MIs ceases after the infusion.1, 2, 4, 5 Rebound hypercoagulability with reactivation of angina and/or MI has not been ruled out with LMWH. If overall mortality is improved with heparins, despite the rebound hypercoagulability and reactivation of unstable angina problem and the serious bleeding risk, then using one of these drugs would be justified. However, if heparin use merely delays MIs until the withdrawal period without reducing mortality, then the additional bleeding risk would move the risk-benefit analysis toward an assessment of net harm.
Over 60% of the subjects in the 8 RCTs in this meta-analysis came from the FRISC study using dalteparin published in 1995. This RCT contains 94% of the subjects receiving LMWHs. The conclusions of this review depend entirely on this RCT. The ACC/AHA 2007 Guideline for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction states, ‘Dalteparin was evaluated for management of patients with UA/NSTEMI in an era before the widespread use of important therapies such as stents, clopidogrel, and GP IIb/IIIa inhibitors. Its relative efficacy and safety in the contemporary management era is not well established.’6 In other words, heparins carry a much higher risk of causing bleeding now than in the early 1990s when FRISC was done.
In the FRISC
trial, dalteparin 120 IU / kg q12 hours was given the
first 6 days and then 7500 IU qd for the next 35-40 days. The incidence of
death or MI in the first 6 days strongly favored dalteparin over placebo
(13/743 versus 36/759, p < 0.001). However, the event rate from days 7-14
after the reduction in dalteparin dose non
significantly favored placebo (13/724 versus 7/721, p = 0.19), suggesting a
rebound effect. At 42 days into the trial just before the maintenance dose of
dalteparin was stopped, the combined endpoint of deaths and MIs only marginally
favored anticoagulation (p = 0.07). At 6 months, the only data point after the
dalteparin was discontinued, there was no significant difference in the
combined death and MI endpoint (p = 0.41). Deaths were not significantly
different (placebo: 41/749 versus dalteparin: 39/726).
In conclusion,
since injectable anticoagulants do not reduce mortality in acute coronary
syndrome and merely delay heart attacks until after the infusion, the risk of
major, permanently disabling, and fatal bleeding (much greater now than when
these studies were done) is not justified.
1. Theroux P, Ouimet
H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. New England Journal of
Medicine. 1988;319:1105-1111.
2. Risk of myocardial infarction and death during treatment
with low-dose aspirin and intravenous heparin in men with unstable coronary
artery disease. The RISC Group. Lancet. 1990;336:830-837.
3. Theroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation
of unstable angina after the discontinuation of heparin. N Engl J Med. July 16, 1992;327(3):141-145.
4. Cohen M, Adams P, Parry G, et al. Combination antithrombotic
therapy in unstable rest angina and non-Q- wave infarction in nonprior aspirin
users. Primary end points analysis from the ATACS trial.
Antithrombotic Therapy in Acute Coronary Syndromes Research
Group. Circulation. January 1, 1994;89(1):81-88.
5. Theroux P, Waters D, Qiu S, McCans J, de Guise P, Juneau M.
Aspirin versus heparin to prevent myocardial infarction during the acute phase
of unstable angina. Circulation. November 1, 1993 1993;88(5):2045-2048.
6. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007
Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation
Myocardial Infarction: A Report of the American College of Cardiology/American
Heart Association Task Force on Practice Guidelines (Writing Committee to
Revise the 2002 Guidelines for the Management of Patients With Unstable
Angina/Non-ST-Elevation Myocardial Infarction) Developed in Collaboration with
the American College of Emergency Physicians, the Society for Cardiovascular
Angiography and Interventions, and the Society of Thoracic Surgeons Endorsed by
the American Association of Cardiovascular and Pulmonary Rehabilitation and the
Society for Academic Emergency Medicine. 10.1016/j.jacc.2007.02.013. J Am Coll Cardiol. August 14, 2007;50(7):e1-157.